Disease relevance of GHSR

• To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity [1].
• Additionally, the coding region of GHSR was systematically screened, and seven sequence variants were identified in 93 obese, 96 normal weight, and 94 underweight individuals and 43 children with short normal stature (SNS) [2].
• Body weights of the transgenic mice became similar in adulthood, whereas adipose mass was reduced, particularly so in female GHRH-GHSR mice [3].
• Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas [4].
• The expression of GHSR mRNA was significantly lower in gsp mutation-positive than -negative adenomas [5].

Psychiatry related information on GHSR

• We demonstrate that GHSR mRNA is up-regulated after food deprivation (48 h) in the hypothalamic arcuate nucleus and ventromedial nucleus of the seasonal Siberian hamster, Phodopus sungorus [6].
• The impaired GH response to ghrelin in anorexia nervosa agrees with previous evidence of blunted GH response to synthetic GH secretagogues and could reflect desensitization of the GHS receptor induced by the chronic elevation of ghrelin levels in this pathological state [7].
• Ghrelin is an endogenous ligand for the GH secretagogue/ghrelin receptor (GHS-R) and stimulates feeding behavior and GH levels in rodents and humans [8].
• Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been shown to promote slow-wave sleep (SWS, non-REM sleep stages 3 and 4) [9].
• Particularly, GHS receptor agonists or antagonists acting on appetite could represent new drug intervention in eating disorders [10].

High impact information on GHSR

• They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently [11].
• Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts [12].
• The GHRP receptor has recently been cloned and it does not show sequence homology with other G-protein-coupled receptors known so far [13].
• This mutation, which results in decreased cell-surface expression of the receptor, selectively impairs the constitutive activity of the GHSR, while preserving its ability to respond to ghrelin [14].
• The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synthetic molecules endowed with GH release properties [14].

Chemical compound and disease context of GHSR

• Furthermore, OVX increased food intake and body weight in wild-type mice, but not in Ghsr(-/-) mice, suggesting that OVX increases food intake by releasing ghrelin from a tonic inhibitory effect of estradiol [15].
• We devised a method to selectively ablate these neurons in neonatal mice and then tested adult mice for their feeding responses to fasting, mild hypoglycemia, 2-deoxy-d-glucose and a ghrelin receptor agonist [16].
• The GH secretagogue hexarelin improves cardiac function after experimental myocardial infarction either through an increased GH secretion or possibly through a cardiac GHS receptor, although this needs further investigation [17].
• Weight loss agents that modulate appetite through pure central nervous system pathways (e.g., APD356, a selective serotonin receptor agonist) and peripheral signals to central nervous system pathways (e.g., cholecystokinin receptor agonists and ghrelin receptor antagonists) are in preclinical or early phase studies [18].

Biological context of GHSR

• We report the identification of a GHSR missense mutation that segregates with short stature within 2 unrelated families [14].
• Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity [1].
• The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome [1].
• Administration of ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHSR 1a), induces potent stimulating effects on GH secretion and food intake [19].
• Chronic changes in feeding state imposed by food restriction over a period of 12 weeks during long day-length induced increased GHSR gene expression, whereas food restriction for 6 weeks had no effect [6].

Anatomical context of GHSR

• Constitutive overexpression of human GHSR in rat GC cell lines resulted in increased basal phosphoinositol turnover and rendered them responsive to GHS ligands [3].
• OBJECTIVE: Ghrelin and its receptor, growth hormone secretagogue (GHS) receptor (GHSR), are expressed in the normal pituitary gland and various types of pituitary adenoma [5].
• Growth hormone-secretagogue receptor (GHSR) RNA is known to be expressed in the hypothalamus and pituitary [20].
• Analysis of a central nervous system tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more common in high grade tumors compared with low grade ones [21].
• Normal thyroids, thyroid tumors, and cell lines showed ghrelin binding sites by binding localization, in the absence of the specific GHS receptor mRNA (with the exception of one normal thyroid) [22].

Associations of GHSR with chemical compounds

• The apparent sexual dimorphism in GHSR indicates different regulatory effects of sex steroid in young growing SDRs [20].
• High doses of GHRP-2 treatment decreased the levels of both GHRH-R and GHS-R mRNA [23].
• However, non-natural SRIH octapeptide agonists (mainly lanreotide and vapreotide) displace 125I-Tyr-Ala-hexarelin from pituitary binding sites suggesting that an endogenous factor related to SRIH might exist and interact with GHS-R [24].
• This review will summarize the recent progress in small-molecule GHS-R antagonists and offer some insight into this area of research based on the experience at Abbott Laboratories [25].
• The constitutive activity of the ghrelin receptor and of neurotensin receptor 2 through the G(q), phospholipase C pathway was approximately 50% of their maximal capacity as determined through inositol phosphate accumulation [26].

Physical interactions of GHSR

• Ghrelin-binding sites were investigated using reverse transcriptase-polymerase chain reaction to detect its growth hormone secretagogue receptor (GHS-R) mRNA and an in situ-binding localization procedure [22].

Regulatory relationships of GHSR

• While recombinant cell lines that overexpress GHS-R have served as effective research tools for these studies, such cell lines may differ in signaling response to ghrelin compared with hypothalamic or pituitary cells expressing GHS-R [27].
• In these cell cultures, GHRP-induced GH release was suppressed by octreotide [28].
• TRH analog ic-induced food intake in freely fed rats was abolished by either peripheral atropine or ghrelin receptor antagonist (d-Lys-3)-GHRP-6 (10 mumol/kg) or ic Y1 receptor antagonist 122PU91 (10 nmol/5 mul) [29].
• The presence of GHS-R mRNA in cells expressing PRL mRNA is emphasized [30].

Other interactions of GHSR

• Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin [21].
• A cDNA clone was identified encoding a second GHS-R-related gene (GPR39) [31].
• While levels of GHRH-R mRNA increased, GHS-R mRNA levels were decreased by low doses of GHRH and GHRP- 2 for 24 h [23].
• From the human genomic library, a homolog, GPR38, with 52% identity to the GHS-R was isolated [32].
• Our data demonstrate for the first time that cortistatin, a natural peptide related to SRIH, binds to GHS-R and suggest that this factor may play a role in modulating the activity of these receptors [24].

Analytical, diagnostic and therapeutic context of GHSR

• METHODS: The expression levels of human ghrelin mRNA and GHSR mRNA were quantified using a competitive RT-PCR method [5].
• The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility [21].
• Fluorescence in situ hybridization localized the genes for GPR38 and GPR39 to separate chromosomes, distinct from the gene encoding the GHS-R and NT-R type 1 [31].
• METHODS: Ghrelin and types 1a and 1b GHS receptor (GHS-R) were determined at the mRNA and protein levels by RT-PCR, in situ hybridization, immunohistochemistry and enzyme immunoassay in tissues, cell lines and culture medium [33].
• Despite the much-publicized promise of providing a novel approach for anti-obesity treatment, limited progress has been made in developing small-molecule GHS-R antagonists and no such compound has been advanced to clinical trials [25].

References